Graduation Date

Summer 8-14-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Jered Garrison

Abstract

The Gastrin-Releasing Peptide Receptor (BB2r) has been investigated as a diagnostic and therapeutic target for prostate and other cancers due to the high expression level on neoplastic relative to normal tissues. A variety of BB2r-targeted agents have been developed utilizing the bombesin(BBN) peptide, which has shown nanomolar binding affinity to human BB2r. However, as with most of the low-molecular weight, receptor-targeted drugs, a major challenge to clinical translation of BB2r-targeted agents is the low retention at the tumor site due to intrinsically high diffusion and efflux rates. Our laboratory seeks to address this deficiency by developing synthetic approaches to selectively increase retention of BB2r-targeted agents in prostate cancer. Hypoxic regions commonly exist in prostate tumors and many other cancers due to a chaotic vascular architecture which impedes delivery of oxygen. In this dissertation, we explore the incorporation of nitroimidazoles, a hypoxia-selective prodrug which irreversibly binds to intracellular nucleophiles in hypoxic tissues, into the BB2r-targeted agent paradigm. We seek to determine if these agents can increase the long-term retention in the tumor and thereby increase efficacy and clinical potential of BB2r-targeted agents.

To that end, we have developed several generations of hypoxia trapping enhanced BBN analogs. Our first in vitro investigation of hypoxia-enhanced 111In-labeled BBN conjugates demonstrated significantly improved retention in hypoxic PC-3 human prostate cancer cells. However, it was determined that the proximity of the 2-nitroimidazole relative to the pharmacophore had a detrimental impact on BB2r binding affinity. To address the problem, our next generation of radioconjugates contained an extended linker to eliminate steric inhibition. The new design demonstrated substantially improved binding affinity and lower clearance rate of the 2-nitroimidazole containing radioconjugates under hypoxic conditions. In vivo biodistribution studies using a PC-3 xenograft mouse model revealed significant tumor retention enhancement. Further work is needed to clarify the mechanisms of cellular retention and to correlate the tumor hypoxia burden with the retention efficacy.

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